1. Field of the Invention
The present invention relates to novel, readily water-soluble 5-(N-alkyl-.alpha.-hydroxyacyl-amino)-2,4,6-triiodo-isophthalic-acid-bis-( hydroxyalkyl-amides) suitable for use as X-ray contrast agents.
2. Description of the Prior Art
5-Acylamino-2,4,6-triiodo-isophthalic acid diamides and their use in X-ray contrasting materials are disclosed in Swiss Pat. No. 544,551. They contain only simple, unsubstituted aliphatic acyl groups, usually acetyl groups. Some representatives of this group, which contain carbohydrate residues, are readily water-soluble, for example, the 3-acetylamino-5-N-methyl-acetylamino-2,4,6-triiodo-benzoyl-glucosamine, which has become known under the non-proprietary name of METRIZAMIDE. In this connection, see also compound No. 11 of U.S. Pat. No. 3,701,711, British Pat. No. 1,321,591, Swiss Pat. No. 554,551, Austrian Pat. No. 318,134 and German Offenlegungsschrift No. 2,031,724, as well as publications by T. Almen, S. Salvesen, K. Golman: Acta Radiologia Suppl. 335 (1973), 1-13, 233-75, 312-38.
One of the disadvantages with this compound is that it is difficult to obtain. This is because it is present in the form of a mixture of isomers and it is practically impossible to isolate the individual isomers, and primarily because it has relatively little stability in aqueous solutions. This makes the handling of the material difficult and significantly limits its usefulness.
The 1-5-.alpha.-hydroxypropionylamino-2,4,6-triiodophthalic-acid-bis-(1,3-dihy droxyisopropylamide) represents an advance over this compound and has become known under the non-proprietary name of IOPAMIDOL. In this connection, see German Pat. No. 2,547,789, British Pat. No. 1,472,050, U.S. Pat. No. 4,001,323 and the article by Felder et al., IL FARMACO, Ed. Sc. 32, 835-844 (1977). It is distinguished by an essentially simpler structure, by higher stability, by a lower viscosity of its concentrated aqueous solutions and by being more easily isolated. The toxicity of this compound is very low.
Recently, two additional derivatives of 5-acylamino-2,4,6-triiodo-isophthalic acid, namely, 5-(N-2-hydroxyethylacetyl-amino)-2,4,6-triiodoisophthalic-acid-bis-(2,3-di hydroxypropylamide) and 5-(N-2,3-dihydroxypropyl-acetylamino)-2,4,6-triiodoisophthalic-acid-bis-(2 ,3-dihydroxypropylamide), which have similar properties, were disclosed in Belgian patent 855,850. They are derived from the slightly water-soluble 5-acetylamino-2,4,6-triiodoisophthalic-acid-bis-(2,3-dihydroxypropylamide) , the water solubility of which is 1% (w/v) at 20.degree.-40.degree. C. It is therefore not surprising that some pertinent isomers are insoluble in water and therefore, practically unusable (see, for example, Belgian Pat. No. 855,850, pages 21-22).
The developments in recent years have clearly shown that it is extremely difficult and only infrequently possible to find compounds which have the properties required for use in nonionic X-ray contrasting materials. These properties are a true water solubility sufficient for producing stable, that is, not supersaturated, concentrated solutions, maximum general and neurotropic tolerance, minimum osmolality, slight viscosity, maximum stability towards hydrolytic effects and a sufficiently simple structure to make the synthesis economical as well as to simplify the isolation and purification.